Extra-hepatic Morbidity and Mortality in Alcohol-related Liver Disease

Systematic Review and Meta-analysis

Mark D. Theodoreson; Guruprasad P. Aithal; Michael Allison; Mayur Brahmania; Ewan Forrest; Hannes Hagström; Stine Johansen; Aleksander Krag; Alisa Likhitsup; Steven Masson; Anne McCune; Neil Rajoriya; Maja Thiele; Ian A. Rowe; Richard Parker

Disclosures

Liver International. 2023;43(4):763-772.

Abstract and Introduction

Abstract

Background: Alcohol use increases the risk of many conditions in addition to liver disease; patients with alcohol-related liver disease (ALD) are therefore at risk from both extra-hepatic and hepatic disease.

Aims: This review synthesises information about non-liver-related mortality in persons with ALD.

Methods: A systematic literature review was performed to identify studies describing non-liver outcomes in ALD. Information about overall non-liver mortality was extracted from included studies and sub-categorised into major causes: cardiovascular disease (CVD), non-liver cancer and infection. Single-proportion meta-analysis was done to calculate incidence rates (events/1000 patient-years) and relative risks (RR) compared with control populations.

Results: Thirty-seven studies describing 50 302 individuals with 155 820 patient-years of follow-up were included. Diabetes, CVD and obesity were highly prevalent amongst included patients (5.4%, 10.4% and 20.8% respectively). Outcomes varied across the spectrum of ALD: in alcohol-related fatty liver the rate of non-liver mortality was 43.4/1000 patient-years, whereas in alcoholic hepatitis the rate of non-liver mortality was 22.5/1000 patient-years. The risk of all studied outcomes was higher in ALD compared with control populations: The RR of death from CVD was 2.4 (1.6–3.8), from non-hepatic cancer 2.2 (1.6–2.9) and from infection 8.2 (4.7–14.3).

Conclusion: Persons with ALD are at high risk of death from non-liver causes such as cardiovascular disease and non-hepatic cancer.

Introduction

Alcohol-related liver disease (ALD) is common worldwide and a frequent cause of ill health and premature mortality. ALD causes a spectrum of liver disease ranging histologically from hepatic steatosis (alcohol-related fatty liver, AFLD), steatohepatitis (alcohol-related steatohepatitis, ASH) to cirrhosis.^[1] Alcohol-related hepatitis (AH) is an acute manifestation of ALD that is usually diagnosed clinically and is typified by jaundice and liver failure.^[2] Hazardous alcohol intake is associated with many medical conditions^[3] and consequently patients with ALD are at risk of other causes of morbidity and mortality in addition to liver disease.

Our group recently described the natural history of ALD based on published studies of histologically proven disease, where we considered progression of disease and mortality.^[4] The information from these biopsy-based studies allowed us only to describe mortality in broad categories of 'liver-related' and 'non-liver-related'. Extra-hepatic disease in patients with ALD has not been systematically reviewed. The purpose of this analysis was to synthesise the available evidence regarding the rate and risk of extra-hepatic mortality from specific major causes in ALD.

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Abstract and Introduction
Methods
Results
Discussion
References
Sidebar

Table 1. Rates of non-liver and liver-related mortality (events/1000 patient-years).
	Mortality rate (deaths per 1000 patient-years)
	Cardiovascular		Cancer		Infection		All non-liver		Liver		Total mortality
	rate	95% CI	rate	95% CI	rate	95% CI	rate	95% CI	rate	95% CI	rate	95% CI
Overall	8.9	6.3–12.3	10.9	8.2–14.5	7.6	4.9–12.0	35.7	27.9–45.7	47.5	32.6–69.2	101.7	78.5–131.8
Fatty liver	11.4	6.8–19.0	10.2	6.9–15.1	1.6	0.7–3.8	43.4	30.1–62.7	11.5	6.1–21.6	55.6	37.0–83.5
Alcoholic hepatitis	6.2	4.9–7.8	5.8	2.6–13.0	18.3	14.5–23.1	22.5	12.4–41.0	109.5	74.0–160.5	135.2	111.3–164.2
Cirrhosis	12.8	7.3–22.3	13.0	7.5–22.6	4.5	2.0–10.5	41.2	25.7–66.0	79.1	53.1–117.6	120.3	84.8–170.7
Decompensated cirrhosis	3.5	1.7–7.3	8.3	5.6–12.3	10.1	5.7–17.9	35.9	18.4–70.1	99.4	55.9–176.9	135.6	76.7–240.0
All ALD^a	8.4	3.7–19.0	12.1	6.6–22.5	10.5	4.8–22.8	33.4	18.5–60.3	30.0	13.0–69.0	92.5	45.3–188.7

^aAll ALD refers to studies that reported outcomes for alcohol-related liver disease as a whole without describing the stage of disease.

Table 2. Relative risk of non-liver and liver-related mortality in persons with alcohol-related liver disease.
	Relative risk of mortality (compared with control populations)
	Cardiovascular			Cancer			Infection			All non-liver			Liver
	RR	95% CI	p	RR	95% CI	p	RR	95% CI	p>	RR	95% CI	p	RR	95% CI	p
Overall	2.4	1.6–3.8	<.01	2.2	1.6–2.9	<.01	8.2	4.7–14.3	<.01	2.2	1.6–3.1	<.01	74.1	14.3–384.8	<.01
Fatty liver	1.4	1.1–1.7	.02	1.2	0.8–1.6	.38				1.5	1.3–1.7	<.01	53.3	27.1–104.8	<.01
Alcoholic hepatitis	5.0	2.7–9.7	<.01	2.3	1.2–4.3	<.01
Cirrhosis	2.5	1.4–4.6	<.01	2.3	1.5–3.7	<.01	7.8	5.8–10.5	<.01	3.0	1.8–5.0	<.01	90.0	7.4–1099.6	<.01
Decompensated Cirrhosis	4.0	3.6–4.5	<.01	2.2	1.7–2.9	<.01	31.5	11.7–85.1	<.01	2.9	2.6–3.3	<.01	162.7	77.5–341.6	<.01
All ALD^a	1.8	0.4–7.7	.46	2.4	1.0–3.7	.05				1.3	1.1–.6	.02	40.3	14.3–384.8	<.01

^aAll ALD refers to studies that reported outcomes for alcohol-related liver disease as a whole without describing the stage of disease.

Authors and Disclosures

Mark D. Theodoreson¹, Guruprasad P. Aithal^2,3, Michael Allison⁴, Mayur Brahmania⁵, Ewan Forrest⁶, Hannes Hagström⁷, Stine Johansen^8,9, Aleksander Krag^8,9, Alisa Likhitsup^10,11, Steven Masson¹², Anne McCune¹³, Neil Rajoriya¹⁴, Maja Thiele^8,9, Ian A. Rowe^1,15 and Richard Parker¹

¹Leeds Liver Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK
²Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, Faculty of Health Sciences, University of Nottingham, Nottingham, UK
³NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
⁴Liver Unit, Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
⁵Toronto General Hospital, Toronto, Ontario, Canada
⁶Queen Elizabeth Hospital, Glasgow, UK
⁷Karolinska University Hospital, Stockholm, Sweden
⁸Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
⁹Fibrosis, Fatty Liver and Steatohepatitis Research Center Odense (FLASH), Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
¹⁰St Luke's Hospital, Kansas City, Missouri, USA
¹¹University of Missouri School of Medicine, Kansas City, Missouri, USA
¹²The Freeman Hospital, Newcastle, UK
¹³Bristol Royal Infirmary, Bristol, UK
¹⁴The Liver Unit, Queen Elizabeth Hospital, Birmingham, UK
¹⁵Leeds Institute for Medical Research, University of Leeds, Leeds, UK

Correspondence
Dr Richard Parker, Leeds Liver Unit, St James' Hospital, Beckett St, Harehills, Leeds, LS9 7TF, UK. Email: richard.parker@nhs.net

Conflict of Interest Statement
MDT has no conflicts of interest to declare. GA has no conflicts of interest to declare. MA has no conflicts of interest to declare. MB has no conflicts of interest to declare. EF has no conflicts of interest to declare. HH's institution has received research grants from AstraZeneca, EchoSens, Intercept, Gilead, MSD and Pfizer for unrelated work. HH has served as a board advisory member for Gilead and Bristol Myers-Squibb. SJ has no conflicts of interest to declare. AK has no conflicts of interest to declare. AL has no conflicts of interest to declare. SM has no conflicts of interest to declare. AM has no conflicts of interest to declare. NR has no conflicts of interest to declare. MT has received speaker's fees from Echosens, Norgine and Siemens Healthcare. Advisory fee from GE Healthcare. IAR has no conflicts of interest to declare. RP has received speaking fees from Norgine, Siemens and Shionogi, and consulting fees from DURECT.